nehal draz. 1- autograft: from one area to another, same inbividual, no ir 2- syngraft (isograft;...
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Nehal Draz
1- Autograft: from one area to another, same inbividual, NO IR
2- Syngraft (Isograft; Syngeneic): genetically identical individuals, NO IR, Histocompatible
3- Allograft (commonest) two genetically dissimilar individuals, same species, Histoincompatible & rejection
4- Xenograft: donor & recipient from different species Histoincompatible & rejection
Living graft: from a living donor,e.g. liver segment, kidney, BM
Cadaveric graft: from a recently dead individual,e.g. heart, cornea, liver, kidney
Bone marrow is the most immunogenic
Liver is the least immunogenic depending on:
Privileged sites: e.g.cornea No significant IR
Lack of lymphatic drainage
2- Different expression of HLA molecules
1- Lack of suitable APCsIn some tissues
HLA
MHC
Refers to genes encoding HLA proteins
MHC molecules
Refers to the protein HLA
Allelic polymorphism: The MHC genes represents the most
polymorhic genetic system Multiple different allels of the same
gene exist in the human population Different allels of the same gene can
give Ags with slightly distinct sequences
e.g. A gene has 151 allels
1- control IR by MHC restriction
2- targets of IR resulting in cytotoxity in graft rejection
3- Certain MHC allels are associated with some diseases e.g. multiple sclerosis &DR2
Recipient Tcells can recognize donor allo Ags in the graft by 2 different ways:
Recipient Tcells recognize donor;s Ags on donor's MHC molecules on the graft APCs
Donor APCs leave the graft & migrate to the regional lymph nodes
There they activate recipient’s Tcells
The activated Tcells are carried back to the graft which they attack directly
Uptake of donor MHC molecules by the recipient own APCs and presentation to self Tcells on self MHC molecules
CD8 Tcells
CD8 Tcells
CD4 Tcells
CD4 Tcells
- The generated alloreactive CTLS attack graft cells bearing MHC I and destroy them by direct cytotoxicity
Secrete cytokines enhancing graft damage:- IL-2: stimulate CTLs- IFNγ: increase allogenic MHC class I &II on graft cells- IL4, 5, 6 stimulate Ab production by Bcells
CM I
IgG or IgMForeign GRAFT cell
Y1- Opsonization
2- Complement mediated lysis
3- ADCCdestructionMQ NK
HUMORAL
effector phase. cont
1- Hyperacute rejection
2- acute rejection
3- Chronic rejection
Within minutes Circulating preformed
anti ABO or anti-HLA antibodies
Activation of compl. and clotting pathways
No treatment
Prevention: proper matching
Within days or weeks
Treatment: immunosuppression
Prevention: proper matching
TC
CD4
YYYY
Destroy graft cells
Lymphokines activating Infl.& MQ
Endothelial injury
After months or years
No treatment Prevention:
proper matching
Alloantigen in Vessel wall
Proliferation of smoothMuscle cells
Gradual lumen narrowing
ischemia,Interstial fibrosisLoss of function
Delayed type hypersensitivity
CYTOKINES
Histocompatibility testingHistocompatibility testing
Post-operative immunosuppressive therapyPost-operative immunosuppressive therapy
Recipient preparationRecipient preparation
1- ABO typing2- HLA testing: determination of HLA
phenotype for donor & recipient which can be done by:
a) microlymphocytotoxicity test b) HLA molecular typing: PCR c) white cell cross matching: mixed
lymphocytotoxicity test
3- detection of preformed Abs against donor cells in the serum of the recipient
Complete history taking & full clinical examination
Treatment of hypertension if present Treatment of infections if present Prophylactic antibiotics Pre-transplantation
immunosuppressive therapy
The drugs used to suppress the immune system can be divided into 3 categories:
Cytotoxic drugsCytotoxic drugs
Powerful anti-inflammatory drugs (corticosteroid)Powerful anti-inflammatory drugs (corticosteroid)
Fungal & bacterial derivativesFungal & bacterial derivatives
prednisone
-Azathioprine-Cyclophosphamide
-Cyclosporine A-FK506-Rapamycin
Drug Mechanism of action
Cyclosporine & FK 506 Block Tcell cytokine production
Rapamycin Inhibits IL-2 signaling which inhibits lymphocyte proliferation
Corticosteroids Reduce inflammation by inhibiting MQ cytokine secretion
Anti IL-2 receptor Inhibit T cell proliferation by inhibiting IL-2 binding
Anti-CD40 ligand Inhibit cellular activation by blocking co-stimulation
Monoclonal Ab against Tcell surface markers
Depletion of Tcells
Infections
Malignancies: especially lymphomas & carcinoma of the skin
Anaphylaxis or serum sickness
Graft verus host disease (GVHD)
A successful therapy for tumors derived from marrow precursors such as leukemia & lymphomas
It may be also successful in treatment of some primary immunedefficiency disease such as severe forms of thalassemias
In leukemia therapy, the source of leukemia must be first destroyed by aggressive cytotoxic chemotherapy. The patient is thus severely immunocompromised
Bone marrow cells are highly immunogenic& can elicit a strong IR
Therefore, very careful donor/recipient HLA matching is critical
If mature donor Tcells are transplanted with the marrow cells, these mature Tcells recognize the tissues of the recipient as foreign causingsevere inflammatory disease called:
GVHD
Graft Versus Host Disease
-Rashes-Diarrhea-Pneumonitis-Liver dysfunction-Wasting-Death
-Rashes-Diarrhea-Pneumonitis-Liver dysfunction-Wasting-Death
1- The most crucial factor is donor selection &MHC compatibility: an identical twin is the ideal donor
2- From poorly matched grafts, T lymphocytes can be removed using monoclonal Abs. to avoid induction of an immune response by the immune competent (mature) donor Tcells against the tissues of the immunocompromised recipient & hence GVHD
3-Malignant cells should be eliminated from the recipient blood to avoid recurrence of the underlying malignancy which necessitated the BMT in the first place
4- Methotrexate, cyclosporin & prednisone are often used to control GVHD